tbuckley/cabot-search huggingface dataset:
Direct evidence for the involvement of intestinal reactive oxygen species in the progress of depression via the gut-brain axis
Authors: Yutaka Ikeda, Naoki Saigo, Yukio Nagasaki
Journal: Biomaterials (2023)

Depression is a serious global social problem. Various therapeutic drugs have been developed based on the monoamine hypothesis; however, treatment-resistant depression is a common clinical issue. Recently, the gut-brain axis, which is associated with the hypothesis that the intestinal environment affects the brain, has garnered significant interest, and several studies have attempted to treat brain disorders based on this axis. These attempts include fecal transplantation, probiotics and prebiotics. In this study, we focused on intestinal reactive oxygen species (ROS) because excessive ROS levels disturb the intestinal environment. To elucidate the impact of scavenging intestinal ROS on depression treatment via the gut-brain axis, a novel polymer-based antioxidant (siSMAPoTN), which was distributed only in the intestine and did not diffuse into the whole body after oral administration, was used. siSMAPoTN selectively scavenged intestinal ROS and protected the intestinal environment from damage caused by chronic restraint stress (CRS). In addition, siSMAPoTN suppressed physiological and behavioral depression-related symptoms in the CRS mouse model.
Safety and immunogenicity of a protein subunit COVID-19 vaccine (ZF2001) in healthy children and adolescents aged 3–17 years in China: a randomised, double-blind, placebo-controlled, phase 1 trial and an open-label, non-randomised, non-inferiority, phase 2 trial
Authors: Lidong Gao, Yan Li, Peng He, Zhen Chen, Huaiyu Yang, Fangjun Li, Siyuan Zhang, Danni Wang, Guangyan Wang, Shilong Yang, Lihui Gong, Fan Ding, Mengyu Ling, Xilu Wang, Leilei Ci, Lianpan Dai, George Fu Gao, Tao Huang, Zhongyu Hu, Zhifang Ying, Jiufeng Sun, Xiaohu Zuo
Journal: The Lancet Child & Adolescent Health (2023)
Infection rate in Guangzhou after easing the zero-COVID policy: seroprevalence results to ORF8 antigen
Authors: Junyuan Huang, Shi Zhao, Ka Chun Chong, Yingchun Zhou, Weiguo Lu, Fang Fang, Peter Pak Hang Cheung, Kiu Cheung Lai, David SC Hui, Chris Ka Pun Mok
Journal: The Lancet Infectious Diseases (2023)
Evaluation of PXL065 – deuterium-stabilized (R)-pioglitazone in patients with NASH: A phase II randomized placebo-controlled trial (DESTINY-1)
Authors: Stephen A. Harrison, Carole Thang, Sébastien Bolze, Sheila Dewitt, Sophie Hallakou-Bozec, Julie Dubourg, Pierre Bedossa, Kenneth Cusi, Vlad Ratziu, Jean-Marie Grouin, David E. Moller, Pascale Fouqueray
Journal: Journal of Hepatology (2023)
Boosting compromised SARS-CoV-2-specific immunity with mRNA vaccination in liver transplant recipients
Authors: Hendrik Luxenburger, David B. Reeg, Julia Lang-Meli, Matthias Reinscheid, Miriam Eisner, Dominik Bettinger, Valerie Oberhardt, Elahe Salimi Alizei, Katharina Wild, Anne Graeser, Vivien Karl, None Sagar, Florian Emmerich, Florian Klein, Marcus Panning, Daniela Huzly, Bertram Bengsch, Tobias Boettler, Roland Elling, Robert Thimme, Maike Hofmann, Christoph Neumann-Haefelin
Journal: Journal of Hepatology (2023)
Risk of Helicobacter pylori transmission by faecal microbiota transplantation via oral capsules
Authors: Anne Karmisholt Grosen, Susan Mikkelsen, Simon Mark Dahl Baunwall, Jens Frederik Dahlerup, Lise Tornvig Erikstrup, Christian Lodberg Hvas, Christian Erikstrup
Journal: Clinical Microbiology and Infection (2023)

The aim was to determine if Helicobacter pylori is transmitted from donors to recipients by faecal microbiota transplantation (FMT) via oral capsules.In a cohort of faeces donors not primarily screened for H. pylori, consecutive stool samples were retrospectively analysed by the H. pylori stool antigen test (SAT). Subsequently, we analysed recipient stool samples collected before and after receiving faeces donated by H. pylori SAT-positive donors, and we recorded recipient use of antibiotics and proton pump inhibitors. All stool samples were frozen upon collection and stored at -80°C until use.Thirteen out of 40 faeces donors (33%; 95% CI, 20-48%) were H. pylori SAT-positive. Among those positive, five donors donated faeces for 28 capsule-based FMTs performed in 26 recipients with stool samples collected before and after FMT. At a median of 59 days (range, 7-84 days) after FMT, no recipients (0%; 95% CI, 0-11%) were H. pylori SAT-positive.We found no occurrence of H. pylori transmission from healthy, asymptomatic donors to recipients by oral capsule-based FMT, although with a wide CI.
IL-21R signal reprogramming cooperates with CD40 and BCR signals to select and differentiate germinal center B cells
Authors: Wei Luo, Laura Conter, Rebecca A. Elsner, Shuchi Smita, Florian Weisel, Derrick Callahan, Shuxian Wu, Maria Chikina, Mark Shlomchik
Journal: Science Immunology (2023)

Both B cell receptor (BCR) and CD40 signaling are rewired in germinal center (GC) B cells (GCBCs) to synergistically induce c-MYC and phosphorylated S6 ribosomal protein (p-S6), markers of positive selection. How interleukin-21 (IL-21), a key T follicular helper (T FH )–derived cytokine, affects GCBCs is unclear. Like BCR and CD40 signals, IL-21 receptor (IL-21R) plus CD40 signals also synergize to induce c-MYC and p-S6 in GCBCs. However, IL-21R plus CD40 stimulation differentially affects GCBC fate compared with BCR plus CD40 ligation—engaging unique molecular mechanisms—as revealed by bulk RNA sequencing (RNA-seq), single-cell RNA-seq, and flow cytometry of GCBCs in vitro and in vivo. Whereas both signal pairs induced BLIMP1 in some GCBCs, only the IL-21R/CD40 combination induced IRF4 hi /CD138 + cells, indicative of plasma cell differentiation, along with CCR6 + /CD38 + memory B cell precursors. These findings reveal a second positive selection pathway in GCBCs, document rewired IL-21R signaling in GCBCs, and link specific T FH - and Ag-derived signals to GCBC differentiation.
Heparan sulfate regulates IL-21 bioavailability and signal strength that control germinal center B cell selection and differentiation
Authors: Zhian Chen, Yanfang Cui, Yin Yao, Bo Liu, Joseph Yunis, Xin Gao, Naiqi Wang, Pablo F. Cañete, Zewen Kelvin Tuong, Hongjian Sun, Hao Wang, Siling Yang, Runli Wang, Yew Ann Leong, David Simon Davis, Jiahuan Qin, Kaili Liang, Jun Deng, Conan K. Wang, Yen-Hua Huang, Jonathan A. Roco, Sam Nettelfield, Huaming Zhu, Huajun Xu, Zhijia Yu, David Craik, Zheng Liu, Hai Qi, Christopher Parish, Di Yu
Journal: Science Immunology (2023)

In antibody responses, mutated germinal center B (B GC ) cells are positively selected for reentry or differentiation. As the products from GCs, memory B cells and antibody-secreting cells (ASCs) support high-affinity and long-lasting immunity. Positive selection of B GC cells is controlled by signals received through the B cell receptor (BCR) and follicular helper T (T FH ) cell–derived signals, in particular costimulation through CD40. Here, we demonstrate that the T FH cell effector cytokine interleukin-21 (IL-21) joins BCR and CD40 in supporting B GC selection and reveal that strong IL-21 signaling prioritizes ASC differentiation in vivo. B GC cells, compared with non-B GC cells, show significantly reduced IL-21 binding and attenuated signaling, which is mediated by low cellular heparan sulfate (HS) sulfation. Mechanistically, N-deacetylase and N-sulfotransferase 1 (Ndst1)–mediated N-sulfation of HS in B cells promotes IL-21 binding and signal strength. Ndst1 is down-regulated in B GC cells and up-regulated in ASC precursors, suggesting selective desensitization to IL-21 in B GC cells. Thus, specialized biochemical regulation of IL-21 bioavailability and signal strength sets a balance between the stringency and efficiency of GC selection.
Immunosuppressive reprogramming of neutrophils by lung mesenchymal cells promotes breast cancer metastasis
Authors: Zheng Gong, Qing Li, Jiayuan Shi, Peishan Li, Li Hua, Leonard D. Shultz, Guangwen Ren
Journal: Science Immunology (2023)

Neutrophils, the most abundant innate immune cells, function as crucial regulators of the adaptive immune system in diverse pathological conditions, including metastatic cancer. However, it remains largely unknown whether their immunomodulatory functions are intrinsic or acquired within the pathological tissue environment. Here, using mouse models of metastatic breast cancer in the lungs, we show that, although neutrophils isolated from bone marrow (BM) or blood are minimally immunosuppressive, lung-infiltrating neutrophils are robustly suppressive of both T cells and natural killer (NK) cells. We found that this tissue-specific immunosuppressive capacity of neutrophils exists in the steady state and is reinforced by tumor-associated inflammation. Acquisition of potent immunosuppression activity by lung-infiltrating neutrophils was endowed by the lung-resident stroma, specifically CD140a + mesenchymal cells (MCs) and largely via prostaglandin-endoperoxide synthase 2 (PTGS2), the rate-limiting enzyme for prostaglandin E 2 (PGE 2 ) biosynthesis. MC-specific deletion of Ptgs2 or pharmacological inhibition of PGE 2 receptors reversed lung neutrophil–mediated immunosuppression and mitigated lung metastasis of breast cancer in vivo. These lung stroma–targeting strategies substantially improved the therapeutic efficacy of adoptive T cell–based immunotherapy in treating metastatic disease in mice. Collectively, our results reveal that the immunoregulatory effects of neutrophils are induced by tissue-resident stroma and that targeting tissue-specific stromal factors represents an effective approach to boost tissue-resident immunity against metastatic disease.
Effectiveness of a warm-up programme to reduce injuries in youth volleyball players: a quasi-experiment
Authors: Evert Verhagen, Ingrid Vriend, Vincent Gouttebarge, Ellen Kemler, Jacqueline de Wit, Daniel Zomerdijk, Joske Nauta
Journal: British Journal of Sports Medicine (2023)

To establish the effectiveness of the 'VolleyVeilig' programme on reducing injury rate, injury burden and injury severity in youth volleyball players.We conducted a quasi-experimental prospective study over one season of youth volleyball. After randomisation by competition region, we instructed 31 control teams (236 children, average age 12.58±1.66) to use their usual warm-up routine. The 'VolleyVeilig' programme was provided to 35 intervention teams (282 children, average age 12.90±1.59). This programme had to be used during each warm-up before training sessions and matches. We sent a weekly survey to all coaches, collecting data on each player's volleyball exposure and injuries sustained. Multilevel analyses estimated differences in injury rates and burden between both groups, and we used non-parametric bootstrapping to compare the differences in injury numbers and injury severity.We found an overall reduction in injury rates of 30% for intervention teams (HR 0.72; 95% CI 0.39 to 1.33). Detailed analyses revealed differences for acute (HR 0.58; 95% CI 0.34 to 0.97) and upper extremity injuries (HR 0.41; 95% CI 0.20 to 0.83). Compared with control teams, the intervention teams had a relative injury burden of 0.39 (95% CI 0.30 to 0.52) and a relative injury severity of 0.49 (95% CI 0.03 to 0.95). Only 44% of teams fully adhered to the intervention.We established that the 'VolleyVeilig' programme was associated with reduced acute and upper extremity injury rates and lower injury burden and severity in youth volleyball players. While we advise implementation of the programme, programme updates to improve adherence are needed.
Proteinase 3 promotes formation of multinucleated giant cells and granuloma-like structures in patients with granulomatosis with polyangiitis
Authors: Scott R Henderson, Harry Horsley, Paul Frankel, Maryam Khosravi, Talya Goble, Stephen Carter, Marilina Antonelou, Rhys D R Evans, Xiang Zhang, Tai-Ying Chu, Hsi-Hsien Lin, Siamon Gordon, Alan David Salama
Journal: Annals of the Rheumatic Diseases (2023)

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are autoimmune vasculitides associated with antineutrophil cytoplasm antibodies that target proteinase 3 (PR3) or myeloperoxidase (MPO) found within neutrophils and monocytes. Granulomas are exclusively found in GPA and form around multinucleated giant cells (MGCs), at sites of microabscesses, containing apoptotic and necrotic neutrophils. Since patients with GPA have augmented neutrophil PR3 expression, and PR3-expressing apoptotic cells frustrate macrophage phagocytosis and cellular clearance, we investigated the role of PR3 in stimulating giant cell and granuloma formation.
What is a response in randomised controlled trials in giant cell arteritis?
Authors: Christian Dejaco, Sofia Ramiro, Zahi Touma, Milena Bond, Medha Soowamber, Catalina Sanchez-Alvarez, Carol A Langford
Journal: Annals of the Rheumatic Diseases (2023)

Glucocorticoids (GCs) are the gold standard for treatment of giant cell arteritis (GCA); however, there is a need for studies on GC-sparing agents, given that up to 85% of patients receiving GC only develop adverse events. Previous randomised controlled trials (RCTs) have applied different primary endpoints, limiting the comparison of treatment effects in meta-analyses and creating an undesired heterogeneity of outcomes. The harmonisation of response assessment is therefore an important unmet need in GCA research. In this viewpoint article, we discuss the challenges and opportunities with the development of new, internationally accepted response criteria. A change of disease activity is a fundamental component of response; however, it is debatable whether the ability to taper GC and/or the maintenance of a disease state for a specific time period, as applied in recent RCTs, should be part of response assessment. The role of imaging and novel laboratory biomarkers as possible objective markers of disease activity needs further investigation but might be a possibility when drugs directly or indirectly influence the levels of traditional acute-phase reactants such as erythrocyte sedimentation rate and C reactive protein. Futures response criteria might be constructed as a multidomain set, but the questions about which domains will be included and what their relative weights will be still need to be answered.
Transcriptomic profiling reveals distinct subsets of immune checkpoint inhibitor induced myositis
Authors: Iago Pinal-Fernandez, Angela Quintana, Jose Cesar Milisenda, Maria Casal-Dominguez, Sandra Muñoz-Braceras, Assia Derfoul, Jiram Torres-Ruiz, Katherine Pak, Stefania Dell'Orso, Faiza Naz, Gustavo Gutierrez-Cruz, Margherita Milone, Shahar Shelly, Yaiza Duque-Jaimez, Ester Tobias-Baraja, Ana Matas-Garcia, Gloria Garrabou, Joan Padrosa, Javier Ros, Ernesto Trallero-Araguás, Brian Walitt, Lisa Christopher-Stine, Thomas E Lloyd, Chen Zhao, Shannon Swift, Arun Rajan, Josep Maria Grau-Junyent, Albert Selva-O'Callaghan, Teerin Liewluck, Andrew Lee Mammen
Journal: Annals of the Rheumatic Diseases (2023)

Inflammatory myopathy or myositis is a heterogeneous family of immune-mediated diseases including dermatomyositis (DM), antisynthetase syndrome (AS), immune-mediated necrotising myopathy (IMNM) and inclusion body myositis (IBM). Immune checkpoint inhibitors (ICIs) can also cause myositis (ICI-myositis). This study was designed to define gene expression patterns in muscle biopsies from patients with ICI-myositis.Bulk RNA sequencing was performed on 200 muscle biopsies (35 ICI-myositis, 44 DM, 18 AS, 54 IMNM, 16 IBM and 33 normal muscle biopsies) and single nuclei RNA sequencing was performed on 22 muscle biopsies (seven ICI-myositis, four DM, three AS, six IMNM and two IBM).Unsupervised clustering defined three distinct transcriptomic subsets of ICI-myositis: ICI-DM, ICI-MYO1 and ICI-MYO2. ICI-DM included patients with DM and anti-TIF1γ autoantibodies who, like DM patients, overexpressed type 1 interferon-inducible genes. ICI-MYO1 patients had highly inflammatory muscle biopsies and included all patients that developed coexisting myocarditis. ICI-MYO2 was composed of patients with predominant necrotising pathology and low levels of muscle inflammation. The type 2 interferon pathway was activated both in ICI-DM and ICI-MYO1. Unlike the other types of myositis, all three subsets of ICI-myositis patients overexpressed genes involved in the IL6 pathway.We identified three distinct types of ICI-myositis based on transcriptomic analyses. The IL6 pathway was overexpressed in all groups, the type I interferon pathway activation was specific for ICI-DM, the type 2 IFN pathway was overexpressed in both ICI-DM and ICI-MYO1 and only ICI-MYO1 patients developed myocarditis.
The nanoformula of zoledronic acid and calcium carbonate targets osteoclasts and reverses osteoporosis
Authors: Fei Jia, Lifo Ruan, Chuanchao Du, Yu Liu, Xiaomeng Cai, Rui Dou, Jiayu Zhang, Xiaoguang Liu, Jun Chen, Xingcai Zhang, Zhifang Chai, Yi Hu
Journal: Biomaterials (2023)
Cobaltosic oxide-polyethylene glycol-triphenylphosphine nanoparticles ameliorate the acute-to-chronic kidney disease transition by inducing BNIP3-mediated mitophagy
Authors: Shaozong Qin, Chi Liu, Yin Chen, Mengying Yao, Shuyi Liao, Wang Xin, Shuiqin Gong, Xu Guan, Yan Li, Jiachuan Xiong, Jing Chen, Yunzhu Shen, Yong Liu, Jinghong Zhao, Yinghui Huang
Journal: Kidney International (2023)
Virtual wards: urgent care policy must follow the evidence
Authors: Dan Lasserson, Tim Cooksley
Journal: BMJ (2023)

NHS urgent and emergency care is under unbearable strain, which is increasingly causing harm to patients. 1 Overcrowding in emergency departments and stasis in acute medical units-driven by workforce and capacity constraints-prevent timely and high quality care. 2 This exacerbates low staff morale, perpetuating burnout and the high absence levels which currently dominate.The covid-19 pandemic and latterly a severe flu season have arguably expedited the crisis, but the spiral of decline in urgent and emergency care has been happening for a decade and, unless urgent action is taken, we may not yet have reached its nadir.
Routine follow-up may not be needed for people undergoing joint replacement surgery
Authors: Helen Saul, Samantha Cassidy, Brendan Deeney, Jemma Kwint, Philip Conaghan
Journal: BMJ (2023)

The studyKingsbury SR, Smith LK, Czoski Murray CJ, et al. Safety of disinvestment in mid- to late-term follow-up post primary hip and knee replacement: the UK SAFE evidence synthesis and recommendations. Health Soc Care Deliv Res 2022;10. doi:10.3310/KODQ0769To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/joint-replacement-many-people-can-safely-wait-10-years-for-follow-up/.
PHGDH-mediated endothelial metabolism drives glioblastoma resistance to chimeric antigen receptor T cell immunotherapy
Authors: Duo Zhang, Albert M. Li, Guanghui Hu, Menggui Huang, Fan Yang, Lin Zhang, Kathryn E. Wellen, Xiaowei Xu, Crystal S. Conn, Wei Zou, Mark Kahn, Seth D. Rhoades, Aalim M. Weljie, Serge Y. Fuchs, Nduka Amankulor, Daniel Yoshor, Jiangbin Ye, Constantinos Koumenis, Yanqing Gong, Yi Fan
Journal: Cell Metabolism (2023)
Global translational induction during NLR-mediated immunity in plants is dynamically regulated by CDC123, an ATP-sensitive protein
Authors: Tianyuan Chen, Guoyong Xu, Rui Mou, George H. Greene, Lijing Liu, Jonathan Motley, Xinnian Dong
Journal: Cell Host & Microbe (2023)

The recognition of pathogen effectors by their cognate nucleotide-binding leucine-rich repeat (NLR) receptors activates effector-triggered immunity (ETI) in plants. ETI is associated with correlated transcriptional and translational reprogramming and subsequent death of infected cells. Whether ETI-associated translation is actively regulated or passively driven by transcriptional dynamics remains unknown. In a genetic screen using a translational reporter, we identified CDC123, an ATP-grasp protein, as a key activator of ETI-associated translation and defense. During ETI, an increase in ATP concentration facilitates CDC123-mediated assembly of the eukaryotic translation initiation factor 2 (eIF2) complex. Because ATP is required for the activation of NLRs as well as the CDC123 function, we uncovered a possible mechanism by which the defense translatome is coordinately induced during NLR-mediated immunity. The conservation of the CDC123-mediated eIF2 assembly suggests its possible role in NLR-mediated immunity beyond plants.
Non-canonical pattern recognition of a pathogen-derived metabolite by a nuclear hormone receptor identifies virulent bacteria in C. elegans
Authors: Nicholas D. Peterson, Samantha Y. Tse, Qiuyu Judy Huang, Khursheed A. Wani, Celia A. Schiffer, Read Pukkila-Worley
Journal: Immunity (2023)

Distinguishing infectious pathogens from harmless microorganisms is essential for animal health. The mechanisms used to identify infectious microbes are not fully understood, particularly in metazoan hosts that eat bacteria as their food source. Here, we characterized a non-canonical pattern-recognition system in Caenorhabditis elegans (C. elegans) that assesses the relative threat of virulent Pseudomonas aeruginosa (P. aeruginosa) to activate innate immunity. We discovered that the innate immune response in C. elegans was triggered by phenazine-1-carboxamide (PCN), a toxic metabolite produced by pathogenic strains of P. aeruginosa. We identified the nuclear hormone receptor NHR-86/HNF4 as the PCN sensor in C. elegans and validated that PCN bound to the ligand-binding domain of NHR-86/HNF4. Activation of NHR-86/HNF4 by PCN directly engaged a transcriptional program in intestinal epithelial cells that protected against P. aeruginosa. Thus, a bacterial metabolite is a pattern of pathogenesis surveilled by nematodes to identify a pathogen in its bacterial diet.
Development of top-down cortical propagations in youth
Authors: Adam Pines, Arielle S. Keller, Bart Larsen, Maxwell Bertolero, Arian Ashourvan, Dani S. Bassett, Matthew Cieslak, Sydney Covitz, Yong Fan, Eric Feczko, Audrey Houghton, Amanda R. Rueter, Manish Saggar, Golia Shafiei, Tinashe M. Tapera, Jacob Vogel, Sarah M. Weinstein, Russell T. Shinohara, Leanne M. Williams, Damien A. Fair, Theodore D. Satterthwaite
Journal: Neuron (2023)
HIV rapidly targets a diverse pool of CD4+ T cells to establish productive and latent infections
Authors: Pierre Gantner, Supranee Buranapraditkun, Amélie Pagliuzza, Caroline Dufour, Marion Pardons, Julie L. Mitchell, Eugène Kroon, Carlo Sacdalan, Nicha Tulmethakaan, Suteeraporn Pinyakorn, Merlin L. Robb, Nittaya Phanuphak, Jintanat Ananworanich, Denise Hsu, Sandhya Vasan, Lydie Trautmann, Rémi Fromentin, Nicolas Chomont
Journal: Immunity (2023)
Interplay between liver and blood stages of Plasmodium infection dictates malaria severity via γδ T cells and IL-17-promoted stress erythropoiesis
Authors: Ângelo Ferreira Chora, Sofia Marques, Joana Lisboa Gonçalves, Priscila Lima, Daniel Gomes da Costa, Daniel Fernandez-Ruiz, Maria Inês Marreiros, Pedro Ruivo, Tânia Carvalho, Ruy M. Ribeiro, Karine Serre, William R. Heath, Bruno Silva-Santos, Ann T. Tate, Maria M. Mota
Journal: Immunity (2023)

Plasmodium replicates within the liver prior to reaching the bloodstream and infecting red blood cells. Because clinical manifestations of malaria only arise during the blood stage of infection, a perception exists that liver infection does not impact disease pathology. By developing a murine model where the liver and blood stages of infection are uncoupled, we showed that the integration of signals from both stages dictated mortality outcomes. This dichotomy relied on liver stage-dependent activation of Vγ4+ γδ T cells. Subsequent blood stage parasite loads dictated their cytokine profiles, where low parasite loads preferentially expanded IL-17-producing γδ T cells. IL-17 drove extra-medullary erythropoiesis and concomitant reticulocytosis, which protected mice from lethal experimental cerebral malaria (ECM). Adoptive transfer of erythroid precursors could rescue mice from ECM. Modeling of γδ T cell dynamics suggests that this protective mechanism may be key for the establishment of naturally acquired malaria immunity among frequently exposed individuals.